Derivatives of imidazolidin-2-ones and -2-thiones

ABSTRACT

THERE ARE DISCLOSED HEREIN DERIVATIVES OF IMIDAZOLIDIN-2ONES AND -2-THIONES OF THE FORMULA I   1-(R1-N(-R2)-),2-(X=),4-(R5-N=),5-R3,5-R4-IMIDAZOLIDINE   AND THEIR ACID ADDITION SALTS WITH PHARMACOLOGICALLY ACCEPTABLE ACIDS, IN WHICH R1 IS HYDROGEN OR LOWER ALKYL; R2 IS LOWER ALKYL, NITROTHIAZOLYL, OR NITROFURYL; OR R1 AND R2 TOGETHER WITH THE NITROGEN TO WHICH THEY ARE ATTACHED ARE A HETEROCYCLIC GROUP CONTAINING 4-6 CARBON ATOMS, OR 4 CARBON ATOMS AND AN ADDITIONAL NITROGEN ATOM WHICH MAY OPTIONALLY BE SUBSTITUTED WITH A LOWER ALKYL GROUP, OR 4 CARBON ATOMS AND AN OXYGEN ATOM, R3 IS HYDROGEN OR LOWER ALKYL; R4 IS LOWER ALKYL OR ARALKYL, OR R3 AND R4 TOGETHER WITH THE CARBON ATOM 5 OF THE IMIDAZOLIDINE RING TO WHICH THEY ARE ATTACHED ARE A CARBOCYCLIC RING CINTAINING 5-6 CARBON ATOMS ATTACHED IN SPIRO FASHION TO SAID IMIDAZOLIDINE RING; R5 IS LOWER ALKYL OR CYCLOALKL CONTAINING FROM 5-6 CARBON ATOMS; AND X IS AN OXYGEN OR A SULFUR ATOM. THE COMPOUNDS OF THIS INVENTION POSSESS POSITIVE INOTROPIC ACTIVITY AND ARE USEFUL AS CARDIAC STIMULANTS.

United States Patent Office 3,707,472 Patented Dec. 26, 1972 US. Cl.260-293.7 13 Claims ABSTRACT OF THE DISCLOSURE There are disclosedherein derivatives of imidazolidin-2- ones and -2-thiones of the FormulaI and their acid addition salts with pharmacologically acceptable acids,in which R is hydrogen or lower alkyl; R is lower alkyl, nitrothiazolyl,or nitrofuryl; or R and R together with the nitrogen to which they areattached are a heterocyclic group containing 4-6 carbon atoms, or 4carbon atoms and an additional nitrogen atom which may optionally besubstituted with a lower alkyl group, or 4 carbon atoms and an oxygenatom, R is hydrogen or lower alkyl; R is lower alkyl or aralkyl, or Rand R together with the carbon atom 5 of the imidazolidine ring to whichthey are attached are a carbocyclic ring containing 5-6 carbon atomsattached in spiro fashion to said imidazolidine ring; R is lower alkylor cycloalkyl containing from 56 carbon atoms; and X is an oxygen or asulfur atom. The compounds of this invention possess positive inotropicactivity and are useful as cardiac stimulants.

BACKGROUND OF THE INVENTION This invention relates to derivatives ofimidazolidin-2- ones and -2-thiones of the Formula I and to their acidaddition salts with pharmacologically acceptable acids, in which R ishydrogen or lower alkyl; R is lower alkyl, nitrothiazolyl, ornitrofuryl; or R and R together with the nitrogen to which they areattached are a heterocyclic group containing 4-6 carbon atoms, or 4carbon atoms and an additional nitrogen atom which may optionally besubstituted with a lower alkyl group, or 4 carbon atoms and an oxygenatom, for example a piperidino, azepino, N -methylpiperazino, or amorpholino group; R is hydrogen or lower alkyl; R is lower alkyl oraralkyl, for example benzyl or a-methylbenzyl; or R and R together withthe carbon atom 5 of the imidazolidine ring to which they are attachedare a carbocyclic ring containing 5-6 carbon atoms attached in spirofashion to said imidazolidine ring; R is lower alkyl or cycloalkylcontaining from 5-6 carbon atoms; and X is an oxygen or a sulfur atom.

More particularly, one embodiment of this invention relates to compoundsof the Formula I wherein R and R each is hydrogen or lower alkyl; R islower alkyl; R is lower alkyl or phenyl(lower)alkyl; R is lower alkyl orcycloalkyl of 5 to 6 carbon atoms; and X is oxygen or sulfur; or thepharmaceutically acceptable acid addition salt of such a compound.Another embodiment of this invention relates to compounds of the FormulaI wherein R is hydrogen or lower alkyl; R is lower alkyl; R and Rtogether form a bivalent radical selected from the group consisting oftetramethylene and pentamethylene, R is lower alkyl or cycloalkyl of 5to 6 carbon atoms; and X is oxygen or sulfur; or the pharmaceuticallyacceptable acid addition salt of such a compound. An additionalembodiment of this invention relates to compounds of the Formula Iwherein R and R together with the nitrogen to which they are attachedare piperidino; R is hydrogen or lower alkyl; R is lower alkyl; R islower alkyl or cycloalkyl of 5 to 6 carbon atoms; and X is oxygen orsulfur; or the pharmaceutically acceptable acid addition salt of such acompound.

The compounds of this invention possess positive inotropic activity andare useful as cardiac stimulants, especially in the treatment of cardiacinsufiiciency, of shock, and of conditions associated with low cardiacoutput.

Compounds which may be considered as being somewhat related to thecompounds of this invention of Formula I, but which differ principallyin having R representing an acyl group, such as the formyl, benzoyl, orbenzenesulfonyl group, with R being hydrogen, have been described by I.Ugi in Angew. Chemie, Int. Ed., Vol. 1, p. 8 (1962), in particular pp.18-19, and by Ugi et al. in Liebigs Ann. Chem. Vol. 666, p. 54 (1963).However, those latter compounds ditfer significantly from the compoundsof this invention in possessing a non-basic, essentially neutralacylamino (amide) function attached to position 1 of the imidazolidinering, while the compounds of this invention have in that same position asecondary or tertiary substituted amino group or a nitrogen-containingheterocyclic group attached to position 1 through its tertiary nitrogenatom. The fundamental differences in chemical and physical propertiesbetween an acylamino (amide) function, such as present in position 1 ofthe compounds described by Ugi et al., and a secondary or tertiary aminofunction as present in position 1 of the compounds of this invention arewell known and fully recognized in the art. For example, the acylamino(amide) function is essentially neutral, while in contradistinctionthereto the secondary or tertiary amino group in position 1 of thecompounds of this invention is basic in nature. Moreover, the compoundsdescribed by Ugi et al., do not possess the pharmacological propertiesof the compounds of this invention, nor is there any suggestion to befound in the literature that they might perhaps possess cardiacstimulating activities.

SUMMARY OF THE INVENTION The compounds of this invention of Formula Iare conveniently prepared in the following manner.

A substituted hydrazine of the Formula H in which R and R are as definedin the first instance is condensed with a carbonyl compound of theFormula III in which R and R are as defined in the first instance toyield the corresponding hydrazone of Formula IV in which R R R and R areas defined above. Said last-named hydrazone is treated with anisonitrile of the formula R NC in which R is as defined in the firstinstance, in the presence of an acid of the formula HCNX in which X isas defined in the first instance, to yield the corresponding compound ofFormula I which may, in turn, be treated with a pharmacologicallyacceptable acid to obtain the corresponding acid addition salt. Thefollowing formulae will illustrate this invention.

The compounds of this invention of Formula I and their acid additionsalts with pharmacologically acceptable acids, which arepharmacologically equivalent to the compounds themselves, possessvaluable pharmacological properties. More particularly, these compounds,in standard pharmacological tests, for example in a procedure similar tothat described by S. Garb, M. Penna, and A. Ganz, Amer. J. Physiol., 185(2), p. 332 (1956), for the testing of agents possessing positiveinotropic activity have exhibited such activity and are useful ascardiac stimulants in the treatment of cardiac insufiiciency, of shock,and of conditions associated with low cardiac output.

When the compounds of this invention are employed as cardiac stimulantsin warm-blooded animals, e.g. in rats, alone or in combination withpharmacologically acceptable carriers, the dosage of the compounds andthe proportion of carriers is determined by the solubility and chemicalnature of the compound, by the chosen route of administration and bystandard biological practice. For example, the compounds may beadministered orally in solid form containing such excipients as starch,lactose, certain types of clay, lubricants such as magnesium stearate,and similar ingredients. They may also be administered orally in theform of solutions, or they may be injected parenterally. For parenteraladministration the compounds of this invention may be administered inthe form of sterile solutions containing other solutes, for example,sodium chloride or glucose to make the solution isotonic.

The dosage of the compounds of this invention will vary with the form ofadministration and the particular compound chosen, as well as with theparticular host under treatment. Generally, treatment is initiated withsmall dosages substantially less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached.

In general, the compounds of this invention are most desirablyadministered at a concentration dosage level Which will generally affordeifective results Without causing any harmful side effects, andpreferably at a level that is in a range of from about mg. to about 100mg. per kilo body weight per day, although certain variations will occuras noted above. However, a dosage level in which the range is about mg.to about 50 mg. per kilo body weight per day is most desirably employedin order to achieve effective results.

DETAILED DESCRIPTION OF THE INVENTION More specifically, a substitutedhydrazine of the Formula II, for example an N,N-di(loweralkyl)hydrazine, N-aminopiperidine, N-aminoazepine, or N -amino-Nmethylpiperazine is condensed with a carbonyl compound of the FormulaIII, for example an aldehyde or a ketone of the Formula R COR in Which Rand R are as defined in the first instance, or a cyclic ketone such ascyclopentanone or cyclohexanone, to yield the corresponding hydrazone ofthe Formula IV. Said condensation is preferably carried out at anelevated temperature, at or near the reflux temperature of the mixture,in an anhydrous, water-immiscible hydrocarbon solvent, with concomitantphysical removal of water as it is being formed, e.g. by means of aDean-Stark Water separator. Evaporation of the solvent and purificationof the residue, for example by distillation or crystallization, yieldsthe corresponding hydrazone of Formula IV.

Said last-named hydrazone, preferably in a Water-miscible solvent suchas a lower alkanol, is treated with cyanic or thiocyanic acid in thepresence of an isonitrile of the formula R NC such as a lower alkyl,cyclopentyl, or cyclohexyl isonitrile, to yield the correspondingimidazolidin-2-one or -2-thione of the Formula I. This reaction iscarried out at a temperature below room temperature, preferably withinthe range of from 20 C. to 20 C. Moreover, it is advantageous to useaqueous solutions of alkali metal salts of cyanic or thiocyanic acidinstead of the free acids, and to generate such acids from theirrespective alkali metal salts by addition of a mineral acid, preferablyhydrochloric acid. The reaction is allowed to proceed for periods oftime of from one hour to several days, whereupon a base, preferablyammonia, is added and the corresponding irnidazolidin-Z-one or -2-thioneis isolated by filtration or by solvent extraction followed byevaporation of the solvent, and purified by crystallization.

Said last-named imidazolidin-Z-ones or 2thiones may be treated with apharmacologically acceptable acid, for example, with hydrogen chloridein solution in a lower alkanol or in ether, to obtain the correspondingacid addition salt. Said last-named salts are pharmacologicallyequivalent to the compounds of Formula I and may advantageously :be usedin their place.

In this .manner, when using as starting materials e.g.N,N-dimethylhydrazine and n-butyraldehyde, isobutyraldehyde, or2-phenylpropionaldehyde there are obtained the corresponding hydrazones,i.e. N,N-dimethyl-n-butyl, N,N-dimethylisobutyl, andN,N-dimethyl-Z-phenylpropyl hydrazone, respectively. When reacting saidhydrazones with e.g. cyclohexylisonitrile and potassium cyanate orthiocyanate in the manner described above there are obtained4-cyclohexylimino-1-dimethylamino-S-propylimidazolidin-Z-one or-2-thione (I, R =R =CH R R =cyclohexyl, X=O or S),4-cyclol1exylimino-l-dimethylamino-5-isopropylimidazolidin-2-one or-2-thione (I, R =R =CH R =H, R =CH(CH R =cyclohexyl, X=O or S), and4-cyclohexylimino-l-dimethylamino-5-(a-methylbenzyl)-imidazolidin-2-oneor -2-thione (I, R =R =CH R =H, R =CH(CH )(C H R =cyclohexyl X=O or S),respectively. When using as starting materials N-aminopiperidine,N-aminoazepine, or N -amino-N methylpiperazine and isobutyraldehyde or2-phenylpropionaldehyde the hydrazones obtained are piperidinoisobutyl,azepinoisobutyl, and N -methylpiperazino-2-phenylpropyl hydrazone,which, after treatment with cyclohexylisonitrile and potassium cyanateor thiocyanate as above yield 4cyclohexylimino-5-isopropyl-1 piperidinoimidazolidin-Z-one or -2-thione (I, NR R =piperidino,

R =CH(CH R =cyclohexyl, X=O or S), 1-azepino-4-cyclohexylimino-S-isopropylimidazolidin-Z-one or -2-thione (I, NR R=azepino, R =H, R =CH(CH R =cyclohexyl, X=O or S), and4-cyclohexylirnino-l-(4'-methyll'-piperazino)-5-(a-methylbenzyl)irnidazolidin-Z-oneand -2-thione, (I, NR R =4-methyl-l-piperazino, R =H,

R =CH(CH (C H R- =cyclohexyl, X=O or S), respectively.

It will be apparent to those skilled in the art that condensation of asubstituted hydrazine of Formula II with a cyclic ketone of the FormulaIII in which R and R together with the carbonyl group are a carbocyclicring yields the corresponding hydrazone of Formula IV of said cyclicketone.

Treatment of said hydrazone with an acid of the formula HCNX and anisonitrile of the Formula R NC in which X and R are as defined in thefirst instance yields the corresponding compound of Formula I whichshould be regarded as a deriative of an imidazolidin-Z-one or -2-thionepossessing a bivalent substituent in position 5 in the form of acanbocyclic ring attached in spiro fashion to carbon atom 5 of saidimidazolidin-Z-one or -2-thione. However, in accordance with the rulesof nomenclature such compounds are designated in this application asderivatives of 1,3-diazaspiro[4,4]nonane or 1,3-diazaspiro[4,5]decane,depending upon the number of carbon atoms in the carbocyclic ring (5 or6) attached in spiro fashion to carbon atom 5 of the imidazolidin-Z-oneor -2-thione nucleus.

In this manner, when using as starting materials e.g.N,N-dimethylhydrazine and cyclopentanone or cyclohexanone there areobtained N,N-dimethylcyclopentyl hydrazone and N,N-dimethylcyclohexylhydrazone, respectively. Treatment of said hydrazones with e.g.cyclohexylisonitrile and potassium cyanate or thiocyanate yields 4-cyclohexylimino-l-dimethylamino 1,3 diazaspiro[4,4] nonan-Z-one or-2-thione, (I, R =R =CH R m -(cust- R =cyclohexyl, X=O or S), and4-cyclohexylimino-1-dimethyla-mino-1,3-diazaspiro[4,5]decan-2-one or-2-thione, (I, R =R =CH R +R =(CH R =cyclohexyl, X=O or S),respectively.

It should be noted, however, that it is not absolutely essential toprepare and isolate first the hydrazone of Formula IV before condensingit with the appropriate isonitrile R NC and cyanic or thiacyanic acid.In certain cases the hydrazine of Formula II, the carbonyl compound ofFormula III, the isonitrile R NC and an alkali metal cyanate orthiocyanate may be reacted together in solution in a lower alkanol inthe presence of an acid at temperatures from 20 C. to the refluxtemperature of the mixture, to obtain, after working up in the mannerdescribed above, the corresponding imidazolidin-Z-one or -2- thione.

The following examples will illustrate this invention.

Example 1 A mixture of N,N-dimethylhydrazine (21.0 g., 0.35 mole) andn-butyraldehyde (14.4 g., 0.2 mole) in anhydrous benzene (200 ml.) isrefluxed on the steam bath with continuous removal of water (Dean-Starkseparator). When the reaction is complete the solvent is evaporated andthe residue distilled, optionally under reduced pressure, to yieldN,N-dimethyl-n-butyl hydrazone, B.P. 116-122 C./15-17 mm. Hg.

In the same manner and using substantially the same molar proportions ofreactants, but using the starting materials listed below, the followinghydrazones are obtained.

N-NH2(II) B P R R OOR (III) Hydrazone(IV) O./mm. Hg

N N-dtmethyl- Isobutyralde- N ,N-dimethyliso- 118-125/760 hydrazine.hyde. butyl. N-aminodo Plperidinolso- 80-82/15 piperldine. butyl.N-aminoaze lne do Azepinolsobutyl. 92-98/15-17 N N-dimet yl-Cyclohexanone. N ,N-dhnethyl- 177-180/760 ydrazine. cyelohexyl.

Do Z-phenylpro- N,N-dimethyl 108-116/15-17 plonaldehyde.(at-methylphenethyl).

In the same manner, but using N,N-diethyl-N,N-dipropyl,2-(5-nitrothiazoly1), or 2-(5-nitrofuryl)hydrazine, N-aminopiperazine, N-methyl-N -aminopipcrazine, or N- aminomorpholine and treating with anyof the above aldehydes or ketones the following hydrazones are alsoobtained:

N,N-diethyl-, N,N-dipropy1-, 2(5-nitrothiazolyl)-, 2- (5-nitrofuryl)-,piperazino-, N -methylpiperazino-, or morpholino-n-butyl, isobutyl,cyclohexyl, and tit-methylbenzyl hydrazone. In addition, when usingcyclopentanone or phenylacetaldehyde as the carbonyl compound, there arealso obtained N,N-dimethyl-, N,N-diethyl-, N,N- dipropyl-,2-(5-nitrothiazolyl)-, 2-(5-nitrofuryl)-, piperidino-, azepino-,piperazino-, N methylpiperazinm, or morpholino-cyclopentyl or -benzylhydrazones.

Example 2 N,N-dimethyl-n-butyl hydrazone (11.4 g., 0.1 mole) isdissolved in methanol (150 ml.), a solution of potassium cyanate (16.2g., 0.2 mole) in water (30 ml.) is added followed bycyclohexylisonitrile (10.9 g., 0.1 mole), the mixture is cooled in iceand hydrochloric acid (6 N, 20 ml.) is added dropwise with stirring.After 3 hours of stirring with cooling in ice ammonia (4 N, ml.) isadded, the mixture is extracted with methylene chloride, the extractwashed with dilute ammonia and water, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure, to yield4-cyclohexylimino-l-dimethylamino-5-propylimidazolidin-2-one as an oilwith 11131? 3187, 3032, 1685 cm.- Treatment of said compound in solutionin methanol with dry hydrogen chloride, with cooling, yields thecorresponding hydrochloride salt with M.P. -141" C. aftercrystallization from methylene chloride-hexane.

In the same manner, using substantially the same molar proportions ofreactants and substantially the same pa rameters of temperature and ofreaction times the following compounds of Formula I (substitutedimidazolidin-2- ones and -2-thiones or substituted 1,3-diazaspiro[4,4]nonan-2-ones or -2-thiones or substituted 1,3-diazaspiro-[4,5]decan-2-ones or -2-thiones) are obtained.

HCNX Hydrazons (IV) (salt) RN C N,N-dimethyl- KONO Cyclohexyl-4-cyclohexylimino-1-diisobutyl. isonitrile.methylamino-fi-isopropylimjdazolidin-2-one, M.P. 149151.5 0.,hydrochloride M.P. 162 163.? 0. (methanol-acetone). KCNO do4-cyolohexylimino-5-isopropyl-l-piperidinoimidazolidin-Z-one, M.P.193196 0., hydrochloride M.P. 201203 C. (methanol-acetone)AzepiuolsobutyL. KCNO .do4-0yclohexylimmo-l-azepinofi-isopropylimidazolidinone,

11 E32 3192, a035, 1696 emr' Compounds of Formula I Piperidiuoisobutyl.

N,N-dimethyla-methylphenethyl.

N,N-dimethylcyclohexyl.

In the same manner, but using as starting materials the N,N-diethyl,N,N-dipropyl, Z-(S-nitrothiazolyl), 2-(5-nitrofuryl), piperazino, N-methylpiperazino, or morpholino analogs of the hydrazones listed abovetogether with potassium cyanate and cyclohexyl isonitrile, thecorresponding l-diethylamino, l-dipropylamino, 1-[2-(5-nitrothiazolyl)],1[2-(5-nitrofuryl)], l-piperazino, 1-(N methylpiperazino), andl-morpholino analogs of the compounds of Formula I listed above are alsoobtained.

In the same manner, but using as starting material any of thecyclopentyl or benzyl hydrazones described in Example 1, together withpotassium cyanate and cyclohexylisonitrile, there are obtained thecorrespondingly substituted 1,3-diazaspiro[4,4]nonan-2-ones and thecorrespondingly substituted S-benzylimidazolidin-Z-ones of Formula I.

In the same manner, but using as starting materials any of thehydrazones listed above together with cyclopentylisonitrile, methyl,ethyl, or t-butyl isonitrile and potassium cyanate, the4-cyclopentylimino, 4-methylimino, 4- ethylimino, and 4-t-butyliminoanalogs of the compounds of Formula I described above are obtained.

In the same manner, using as starting materials any of the hydrazoneslisted above together with any of the isonitriles listed above andpotassium thiocyanate, there are obtained the 2-thione analogs of theimidaZolidin-2- ones, 1,3-diazaspiro[4,4]nonan-2-ones, and1,3-diazaspiro[4,5]decan-2-ones listed above.

Example 3 A solution of N amino-N methylpiperazine (0.1 mole),2-phenylpropionaldehyde (0.1 mole), and cyclohexylisonitrile (0.1 mole)in methanol (125 ml.) is mixed with potassium cyanate (0.2 mole)dissolved in water (30 ml.). Hydrochloric acid (6 N, 20 ml.) is addeddropwise with stirring at room temperature, and the mixture is stirredat room temperature for 2 days, adding occassionally a few drops ofhydrochloric acid so as to keep it acidic. Ammonia (4 N, 100 ml.) isadded, the mixture is extracted with methylene chloride, the extractswashed With dilute ammonium hydroxide and water, dried over anhydrousmagnesium sulfate, and evaporated under reduced pressure, to yield4-cyclohexylimino l-(4-methyll-piperazino) 5(a-methylbenzyl)-imidazolidin-2-one, M.P. 197-203 C. Treatment of saidlast-named compound with hydrogen chloride in ether solution yields thecorresponding hydrochloride salt, M.P. 236-238 C. (methanol-ethanol) Inthe same manner, but using potassium thiocyanate instead of potassiumcyanate, the corresponding 4-cyclohexylimino-l (4' methyl lpiperazino)-5-(a-methylbenzyl)-imidazolidin-2-thione is also obtained.

Again in the same manner, but using n-butyraldehyde, isobutyraldehyde,phenylacetaldehyde, cyclopentanone, or cyclohexanone instead of2-phenylpropionaldehyde, potassium cyanate or potassium thiocyanate, andcyclopentyl, methyl, ethyl, or t-butyl isonitrile instead ofcyclohexylisonitrile, there are obtained the 4-cyclopentylimino, 4-methylimino, 4-ethylimino, and 4-t-butylimino derivatives of 5-pro-pyl-,5-isopropyl-, or S-benzyl-l-(4'-methyl-1'-piperazino)imidazolidin-Z-ones and 2-thiones, and of 1- (4-methyl-1piperazino) 1,3 diazaspiro[4,4]nonan- 2-one and -2thione, and of1-(4'-methyl-1-piperazino- 1,3-diazaspiro[4,5 decan-2-one and -2-thione.

In the same manner, as above, any of the free bases listed in Example 2or 3 may be treated with solutions of sulfuric, acetic, maleic, orcitric acid to obtain the corresponding sulfate, acetate, maleate, orcitrate salts.

We claim:

1. A compound of the formula R R I IN-CR X=C C=NR5 wherein R and R eachis hydrogen or lower alkyl; R is lower alkyl; R is lower alkyl orphenyl(lower)alkyl; R is lower alkyl or cycloalkyl of 5 to 6 carbonatoms;

and X is oxygen or sulfur; or the pharmaceutically acceptable acidaddition salt of such a compound.

2. 4 cyclohexylimino 1 dimethylamino 5 propylimidazolidin-Z-one, asclaimed in claim 1.

3. The hydrochloride salt of4-cyclohexylimino-1-dimethylamino-5-propylimidazolidin-2-one, as claimedin claim 1.

4. 4 cyclohexylimino 1 dimethylamino 5 isopropylimidazolidin-2-one, asclaimed in claim 1.

5. The hydrochloride salt of4-cyclohexylimino-1-dimethylamino-S-isopropylimidazolidin-Z-one, asclaimed in claim 1.

6. 4 cyclohexylimino 1 dimethylamino 5(ocmethylbenzyl-imidazolidin-2-one, as claimed in claim 1.

7. The hydrochloride salt of 4-cyclohexylimino-l-dimethylamino5-(u-methylbenzyl)-imidazolidin-2-one, as claimed in claim 1.

8. A compound of the formula wherein R is hydrogen or lower alkyl; R islower alkyl; R and R together form a bivalent radical selected from thegroup consisting of tetramethylene and pentamethylene; R is lower alkylor cycloalkyl of 5 to 6 carbon atoms; and X is oxygen or sulfur; or thepharmaceutically acceptable acid addition salt of such a compound.

9. 4 cyclohexylimino 1 dimethylamino 1,3- diazaspiro[4,5]decan-2-one, asclaimed in claim 8.

10. 4 cyclohexylimino 1 dimethylamino 1,3-diazaspiro[4,5]decane-2-thione, as claimed in claim 8.

11. A compound of the formula 1 RZ NNO:R4

X=O C:NR5

wherein R and R together with the nitrogen atom to which they areattached are piperidino; R is hydrogen or lower alkyl; R is lower alkyl;R is lower alkyl or cycloalkyl of 5 to 6 carbon atoms; and X is oxygenor sulfur; or the pharmaceutically acceptable acid addition salt of sucha compound.

12. 4 cyclohexylimino 5 isopropyl 1 -piperidinoimidazolidin-Z-one, asclaimed in claim 11.

13. The hydrochloride salt of 4-cyclohexylimino-5-isopropyl 1piperidinoimidazolidin 2 one, as claimed in claim 11.

References Cited UNITED STATES PATENTS 3,115,499 12/1963 Michels260309.7

FOREIGN PATENTS 942,195 11/1963 Great Britain 260-309.7

OTHER REFERENCES Lempert et al.: Chem. Abst. vol. 65, columns 8893-94(1966).

McKay et al.: Chem. Abst. vol. 17, column 12,470 (1962).

Ugi et al.: I Liebigs Ann. Chem. vol. 666, pp. 54-61 (1963).

Ugi et al.: Angew. Chem. Internat. Ed. vol. 1, pp. 8-21 (1962).

NATALIE TROUSOF, Primary Examiner US. Cl. X.R.

260239 B, 247.1, 247.2 A, 247.5 R, 268 BC, 268 N, 268 H, 293.66, 293.87,309.7, 566 B; 424273, 267

